Temporally Tunable, Enzymatically-responsive Delivery of Pro-angiogenic Peptides from Poly(ethylene glycol) Hydrogels

• Published in: Advanced healthcare materials Vol. 4; no. 13; pp. 2002 - 2011
• Main Authors: Van Hove, Amy H., Antonienko, Erin, Burke, Kathleen, Brown, Edward, Benoit, Danielle S.W.
• Format: Journal Article
• Language: English
• Published: 07-07-2015
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.201500304

Pro-angiogenic drugs hold great potential to promote reperfusion of ischemic tissues and in tissue engineering applications, but efficacy is limited by poor targeting and short half-lives. Methods to control release duration or provide enzymatically-responsive drug delivery have independently improved drug efficacy. However, no material has been developed to temporally control the rate of enzymatically-responsive drug release. To address this void, hydrogels were developed to provide sustained, tunable release of Qk, a pro-angiogenic peptide mimic of vascular endothelial growth factor, via tissue-specific enzymatic activity. After confirmation that sustained delivery of Qk is necessary for pro-angiogenic effects, a variety of previously-identified matrix metalloproteinase (MMP)-degradable linkers were used to tether Qk to hydrogels. Of these, three (IPES↓LRAG, GPQG↓IWGQ, and VPLS↓LYSG) showed MMP-responsive peptide release. These linkers provided tunable Qk release kinetics, with rates ranging from 1.64 to 19.9 × 10
−3
hours
−1
in vitro
and 4.82 to 8.94 × 10
−3
hours
−1
in vivo
. While Qk was confirmed to be bioactive as released, hydrogels releasing Qk failed to induce significant vascularization
in vivo
after one week, likely due to non-enzymatically degradable hydrogels employed. While Qk was the focus of this study, the approach could easily be adapted to control the delivery of a variety of therapeutic molecules.